Cancer is a principal cause of death in the United States and new approaches to prevent or treat the disease are clearly needed. Clinical studies using a tumor selective human adenovirus (ONYX-015) have demonstrated that a replication competent virus can be engineered to be safe, specific and in several cases cause tumor necrosis. These results have prompted evaluation of Herpes Simplex Virus type 1 (HSV-1) as an oncolytic virus. The overall goal of this research is to identify replication competent HSV-1 mutants capable of specifically replicating in cancer cells. Efforts will be focused (aim 1) on testing existing HSV-1 mutants deleted for accessory function(s) which could only be complemented by tumorigenic cells, (aim 2) on assessing the function of tumor suppressor gene p53 in the context of the viral infection (aim 3) on determining conditions for random mutagenesis of the HSV-1 genome. This will be used for phase II studies where unique mutants will be generated and selected based on preferential growth in cancer cells versus normal cells. PROPOSED COMMERCIAL APPLICATION: Replication competent oncolytic HSV-1 will be used to treat cancer. Productive infection by mutant/recombinant viruses will take place specifically in cancer cells causing lysis/necrosis of the tumor. The tumor therapy could be used through local or systemic delivery of the modified virus for specific or broad cancer types depending on the characteristic of the engineered viruses.